This application requests support for continuation of neuroendocrine studies of relevance to depression. The research program includes both preclinical studies designed to provide information on the role and regulation of thyrotropin releasing hormone (TRH) in the central nervous system and clinical studies directed to more extensive assessments of thyroid axis function in depressed patients. Prior studies have produced substantial data suggesting an important role for TRH as a regulator of CNS function, with potential implications for elucidating the biological substrates of depression. In order to obtain information on the localization and regulation of TRH and its interactions with other CNS neurotransmitter systems, a variety of research techniques and strategies will be employed in the rat, including radioimmunoassay, immunocytochemistry, receptor autoradiography and a number of neuropharmacological probes. Clinical studies will extend prior reports suggesting a relationship between the change in the TSH response to TRH administration and long-term clinical course in depressed patients. This relationship will be assessed within the context of a controlled clinical treatment protocol involving desipramine, paired with multiple assessments with the TRH stimulation test. Depressed patients being treated with cognitive therapy will also be studied in a longitudinal manner, as a control for possible effects of tricyclic antidepressant agents on neuroendocrine function. Evaluation of thyroid axis function will be extended by conducting studies of peripheral thyroid hormone metabolism, assessments of physiological parameters of thyroid function, and developing a brain imaging technique to examine uptake and distribution of triiodothyronine in human brain.